SPOTLIGHT ON DR WILLIAM MCEWAN
Affiliations:
Sir Henry Dale Fellow; UK Dementia Research Institute
Research focus: The cellular cytoplasm is an immune environment. It contains anti-microbial defence mechanisms that destroy invading pathogens over the course of minutes and hours. Our research group is asking whether these same mechanisms can be directed to the protein aggregates that commonly occur in neurodegenerative diseases. As large, repetitive protein complexes, these aggregates share commonalities with virus particles. Being able to harness this form of immunity to clear aggregates will tell us a lot about how cells handle aggregates, and may lead to new ideas for therapeutically targeting intracellular protein lesions.
William McEwan
Recent advance from the lab: We have been looking at the protein Tau, which aggregates inside cells during Alzheimer’s and several other neurodegenerative diseases. We found that the intracellular antibody receptor TRIM21 can recognise antibody-bound Tau assemblies that manage to enter the cell. TRIM21 then degrades these assemblies, preventing onward propagation of Tau aggregation (Mukadam et al., Science 2023). More recently with Leo James’ lab at the MRC Laboratory of Molecular Biology we designed gene therapies that make use of TRIM21’s unique behaviour to specifically reduce Tau pathology, while sparing the physiological Tau versions (Benn, Cheng et al., Science 2024; Miller, Papa et al. Cell 2024). We next want to find ways of implementing this strategy as a therapeutic, and to test it against other difficult targets.
Key challenges for the field: The first is delivery. We can make degraders that work very well in preclinical models, but scaling up to the human brain is not straightforward. There are huge strides that will become possible if and when robust viral or other delivery vectors for the CNS are developed. The second is the nature of protein aggregates in experimental models. The lab-based models rely on mutations and over-expression to drive aggregation, but lead to aggregated structures that bear little relevance to those in the human brain. The neurodegeneration field needs models that reproduce the aggregates that cause disease, otherwise we might be researching artefactual systems.
Most exciting basic or clinical breakthrough in the past few years: I was astonished by this recent paper by the group of Ting Han, who searched for the mechanism by which a small molecule called ACE exerted its cell-killing effect on cancer cells (Lu et al., Cell 2024). Using molecular detective work, they found that ACE forced TRIM21 to interact with the nuclear pore, leading TRIM21 to start destroying this complex structure and cause the cells to die. This finding demonstrates how versatile TRIM21 degradation activity can be, and there is now a growing list of its targets, many of which are considered difficult to degrade via other means. It is also an amazing example of how serendipity can independently arrive at similar conclusions as hypothesis-driven research.
Website: ukdri.ac.uk/team/will-mcewan
Published November 2024